Condensed isoquinolines. 37. Heterocyclization using 3-(arylamino)- and 3-(hetarylamino)isoquinolin-1(2H)-ones

Article abstract of DOI:10.1007/s10593-011-0763-7

The reaction of 3-NHR-isoquinolin-1(2H)-ones (R∈=∈Ar) with aromatic aldehydes in the presence of Me3SiCl or in acetic acid leads to the formation of derivatives of dibenzo[b,f][1, 8]naphthyridin-5(6H)- one and benzo[f]isoquino[3,4-b][1, 8]naphthyridine-5,9(6H,7H)-dione. The reaction for R∈=∈Het in the presence of Me3SiCl gives derivatives of 5H-pyrido[1′,2′:1,2]pyrimido[4,5-c]isoquinolin-5-one, benzo[f]isoquinoline[3,4-b][1,8]naphthyridine-5,9[6H,7H]-dione, and derivatives of new heterocyclic systems, 5H-pyrazino[1′,2′:1,2]pyrimido[4,5-c] isoquinolin-5-one, 5H-[1,3]thiazolo[3′,2′:1,2]pyrimido- [4,5-c]isoquinolin-5-one, 5-H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-one, and isoquino[3,4-b]- [1,5]naphthyridin-5(6H)-one. The effect of the structure of substituent R and nature of the substituent in the benzaldehydes on the structure of the reaction products was studied.

Full text of DOI:10.1007/s10593-011-0763-7

Chemistry of Heterocyclic Compounds, Vol. 47, No. 3, June, 2011 (Russian Original Vol. 47, No. 3, March, 2011)
CONDENSED ISOQUINOLINES. 37.* HETEROCYCLIZATION USING
3-(ARYLAMINO)- AND 3-(HETARYLAMINO)ISOQUINOLIN-1(2H)-ONES
L. M. Potikha1**, R. M. Gutsul2, A. S. Plaskon3,
V. A. Kovtunenko1, and A. A. Tolmachev3
The reaction of 3-NHR-isoquinolin-1(2H)-ones (R = Ar) with aromatic aldehydes in the presence of
Me3SiCl or in acetic acid leads to the formation of derivatives of dibenzo[b,f][1,8]naphthyridin-5(6H)-
one and benzo[f]isoquino[3,4-b][1,8]naphthyridine-5,9(6H,7H)-dione. The reaction for R = Het in the
presence of Me3SiCl gives derivatives of 5H-pyrido[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one,
benzo[f]isoquinoline[3,4-b][1,8]naphthyridine-5,9[6H,7H]-dione, and derivatives of new heterocyclic
systems, 5H-pyrazino[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, 5H-[1,3]thiazolo[3',2':1,2]pyrimido-
[4,5-c]isoquinolin-5-one, 5-H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-one, and isoquino[3,4-b]-
[1,5]naphthyridin-5(6H)-one. The effect of the structure of substituent R and nature of the substituent in
the benzaldehydes on the structure of the reaction products was studied.
Keywords: 3-aminoisocarbostyryl, benzo[f]isoquino[3,4-b][1,8]naphthyridine, benzo[f]pyrazolo[3,4-b]-
[1,8]naphthyridine, dibenzo[b,f][1,8]naphthyridine, isoquino[3,4-b][1,5]naphthyridine, pyrazino[1',2':1,2]-
pyrimido[4,5-c]isoquinoline, pyrido[1',2':1,2]pyrimido[4,5-c]isoquinoline, [1,3]thiazolo[3',2':1,2]pyrimido-
[4,5-c]isoquinoline.
Cyclization starting from enamines is one of the approaches to the synthesis of nitrogen heterocycles [2].
The enamine properties of some derivatives of 3-aminoisoquinolin-1(2H)-one (3-aminoisocarbostyryl) have also
been used for heterocyclization [3]. The fusion of a pyrrole or pyridine ring to face c in these cases has been
carried out predominantly by intramolecular acylation or alkylation. In some studies of the properties of
3-amino-2-methyl- and 3-aminoisoquinolin-1(2H)-ones, Ohta [4, 5] and Deady [6] have described the formation
of condensed isoquinolines in reactions with aldehydes or ketones. In the present work, we studied the reaction
of 3-(arylamino)- and 3-(hetarylamino)isoquinolin-1(2H)-ones with aromatic aldehydes.
_______
*For Communication 36, see [1].
**To whom correspondence should be addressed, e-mail: potikha_l@mail.ru.
1Taras Shevchenko National University, 64 Volodymirska St., Kyiv 01033, Ukraine.
2UkrOrgSynthesis Ltd., 29 Shchorsa St., Kyiv 01133, Ukraine, e-mail: rm80@mail.ru.
3Enamine, 23 Alexandra Matrosova St., Kyiv 01133, Ukraine; e-mail: A.Tolmachev@mail.enamine.net.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 417-431, March, 2011. Original
article submitted February 12, 2010.
342
0009-3122/11/4703-0342©2011 Springer Science+Business Media, Inc.

The condensation of 3-aminoisocarbostyryls substituted at the 3-amino group with aldehydes has been
studied previously only in the case of a condensed derivative, namely, benzimidazo[1,2-b]isoquinolin-11(5H)-
one [7, 8]. The corresponding alkylidene and arylidene derivatives were obtained by heating a mixture of the
reagents in DMF or in acetic acid in the presence of a base.
We have established that heating 3-ArNH-isoquinolin-1(2H)-ones 1a and 1b (Scheme 1) and 3-HetNH-
isoquinolin-1(2H)-ones 2a-f (Schemes 2 and 3) with benzaldehydes in DMF under similar conditions does not
yield significant amounts of reaction product. Attempts to obtain condensation products of compounds 1a,b and
2a-f in 2-propanol in the presence of piperidine were also unsuccessful, while carrying out this reaction in acetic
anhydride led predominantly to acylation [9].
Scheme 1
O
O
O
O
4
1
_
.
HCl
ArCHO
Me3SiCl
NH
NH
NH
Cl
NH
+
NH
N
NH
N
H
Ar
Ar
Ar
12
H
18
3
R
R
R
1a,b
R
4a,b
1a
O
O
O
.
HCl
4
OMe
OMe
Ar1
NH
NH
NH
2'
H
Ar1
N
N
N
+
N
1
– NH2Ar1 HCl
.
Ar
N
Ar
Ar
NH
14
NH
O
O
O
6
5a,b
7
1a R = OMe, b R = NO2; 4 a, b Ar = 4-EtOC6H4, a R = OMe, b R = NO2;
5 a Ar = 4-EtOC6H4, b Ar = 4-O2NC6H4; 7 Ar = 4-O2NC6H4
Isoquinolones 2a-f also proved inert when the reaction was carried out in acetic acid (Schemes 2 and 3).
Only heating 3-ArNH-isocarbostyryls 1a and 1b with benzaldehyde in acetic acid (Method A) gave reaction
products (Scheme 1). Thus, the reaction of compound 1a with 4-methoxybenzaldehyde gave 12-(4-
ethoxyphenyl-10-methoxydibenzo[b,f][1,8]naphthyridin-5(6H)-one (4a) in high (78%) yield (Table 1). The
4-arylidene derivative of the type 3 formed in the initial step of this reaction converts to compound 4a as the
result of intramolecular Friedel-Crafts type alkylation and subsequent oxidation of the electrophilic substitution
product. Changes in the spin system of the 4-methoxyaniline fragment in the starting 3-aminoisocarbostyryl [9]
in addition to the GC/MS and elemental analysis data indicated formation of products of aromatic electrophilic
1
substitution. The H NMR spectrum of dibenzo[b,f][1,8]naphthyridine 4a shows three aromatic proton signals
from a 1,2,4-trisubstituted benzene ring (Table 2). The condensation of isocarbostyryl 1a with 4-nitro-
benzaldehyde under the same conditions leads to the formation of a mixture of products, of which the major
343

TABLE 1. Physicochemical Properties of Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °C (solvent)
C
H
N
С25H20N2O3
С24H17N3O4
С34H27N3O4
С32H22N4O5
С32H20N4O5
С21H16ClN3O
С22H18ClN3O2
С23H20ClN3O2
С21H15N3O
74.69
75.74
69.98
70.07
75.43
75.40
70.78
70.84
70.92
71.11
69.68
69.71
67.38
67.43
68.02
68.06
77.48
77.52
74.39
74.35
74.73
74.78
68.15
68.10
70.71
70.77
67.14
67.18
60.57
60.63
5.10
5.08
4.12
4.16
4.98
5.02
4.15
4.09
3.85
3.73
4.50
4.46
4.59
4.63
5.00
4.97
4.60
4.65
4.80
4.82
5.15
5.18
3.78
3.81
4.49
4.53
4.60
4.56
3.25
3.21
2.73
2.70
7.09
7.07
10.23
10.21
7.80
7.76
10.31
10.33
10.32
10.37
11.60
11.61
10.74
10.72
10.38
10.35
12.93
12.91
11.87
11.82
11.40
11.37
15.15
15.13
15.71
15.72
11.21
11.19
14.90
14.89
13.66
13.64
289-290 (EtOH)
>300 (DMF)
78 (А)
4а
64 (B)
60 (B)
24 (B)
4b
>300 (MeCN-EtOH)
>300 (DMF)
5a
28 (А)
45 (B)
5b
>300 (EtOH)
14 (B)
78 (B)
80 (B)
80 (B)
72 (C)
75 (C)
70 (C)
68 (C)
73 (C)
83 (C)
30 (C)
72 (B)
44 (C)
73 (B)
71 (B)
48 (B)
76 (B)
7
8a*
8b*
8c*
9a
>300 (DMF)
>300 (DMF)
>300 (DMF)
296-298 (EtOH)
247-248 (EtOH)
212-214 (EtOH)
183-184 (DMF)
180-181 (i-PrOH)
178-180 (EtOH)
206-208 (EtOH)
>300 (EtOH)
С22H17N3O2
С23H19N3O2
С21H14N4O3
С21H16N4O2
С21H17N3O2S
С19H12N4O3S
9b
9c
9d
10
11a*2
11b*2
13*3
14
С19H11ClN4O3S 55.50
55.55
76.67
76.71
71.50
71.48
71.82
71.86
65.39
65.45
74.72
74.78
С25H17N3O2
С23H22N4O2
С23H20N4O2
С21H15N5O3
С23H19N3O2
4.40
4.38
5.71
5.74
5.21
5.24
3.90
3.92
10.72
10.74
14.52
14.50
14.58
14.57
18.18
18.17
>300 (DMF)
249-251 (EtOH)
284-285 (DMF)
>300 (DMF)
15a
16a
16b
17
5.20
5.18
11.36
11.37
218-220 (dec.) (EtOH)
_______
*Analysis data for Cl, found/calculated, %: 8a – 9.83/9.80, 8b –8.57/9.05 (dec.),
8c – 8.72/8.73.
*2Analysis data for S, found/calculated, %: 11a – 8.58/8.54, 11b – 8.57/8.52.
*3Analysis data for Cl and S, found/calculated, %: Cl – 8.61/8.63, S – 7.85/7.81.
component 7-(4-methoxyphenyl)-14-(4-nitrophenyl)-8,14-dihydrobenzo[f]isoquino[3,4-b][1,8]napthyridine-
5,9(6H,7H)-dione (5b) was isolated. The formation of derivatives of benzo[f]isoquino[3,4-b][1,8]naphthyridine
has been observed early in the condensation of 3-amino-2-methylisoquinolin-1(2H)-one with aromatic
aldehydes in acetic acid [4, 5]. This result is apparently the consequence of intramolecular cyclization of
Mannich adduct of the type 6 formed in the reaction of intermediate 3 activated by protonation with a molecule
1
of starting isocarbostyryl 1a. The H NMR spectrum of product 5b displays a sole one-proton singlet for H-14,
while all aromatic proton signals have double intensity, which corresponds to a molecule with very high
344

symmetry (Table 3). The signal of the NH groups at 9.25 ppm is very broad and shifted upfield relative to the
amide proton in starting isocarbostyryl 1a at 10.64 ppm [9] due to rapid exchange with water present in the
DMSO-d6 solvent.
Carrying out this reaction in the presence of Me3SiCl is a convenient method for the condensation of
aldehydes with CH-acids, leading to products in high yield [10, 11]. We have found that heating isocarbostyryl
1a with 4-methoxybenzaldehyde in anhydrous DMF in the presence of Me3SiCl (Method B) leads to a mixture
of reaction products, the major component of which is dibenzo[b,f][1,8]naphthyridine derivative 4a in 64%
yield. The second product isolated from the reaction mixture in low (24%) yield, namely, 14-(4-ethoxyphenyl)-
7-(4-methoxyphenyl)-8,14-dihydrobenzo[f]isoquino[3,4-b][1,8]naphthyridine-5,9(6H,7H)-dione (5a), has low
solubility in polar solvents such as ethanol and acetone. We should note that dione 5a is also formed when the
1
reaction is carried out in acetic acid but in yield less than 10% as indicated by the H NMR spectrum of the
reaction mixture. The yield of the product of the condensation of isocarbostyryl 1a with 4-nitrobenzaldehyde is
benzo[f]isoquino[3,4-b]naphthyridine 5b is higher (45%) when the reaction is carried out in the presence of
Me3SiCl than when the reaction is carried out in acetic acid (28% yield) (Table 1). Furthermore, the reaction of
Scheme 2
O
O
NH
NH
N
N
Ar
9a–d
N
N
4-MeOC6H4
N
10
1) Me3SiCl
2) Et3N
Et3N
O
O
O
4
1
4
1
Me3SiCl
NH
NH
Me3SiCl
NH
ArCHO
.
+
HCl
.
HCl
NH
N
N
13
12
Het
2a–c
Ar
8a–d
N
4-EtOC6H4
N
S
Me3SiCl
12a
Et3N
O
O
O
Et3N
NH
N
N
NH
+
.
HCl
S
N
N
N
+
Ar
4-O2NC6H4
13
N
4-O2NC6H4
N
S
SH
_
Cl
11a,b
12b
N
N
, b Het =
2 a Het =
, c Het =
S
N
N
8, 9 a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 4-EtOC6H4, d Ar = 4-O2NC6H4,
11 a Ar = 4-EtOC6H4, b Ar = 4-O2NC6H4
345

1a with 4-nitrobenzaldehyde in the presence of Me3SiCl gave an additional product, namely, 7-(4-methoxyphenyl)-
14-(4-nitrophenyl)benzo[f]isoquino[3,4-b][1,8]naphthrydine-5,9(6H,7H)-dione (7). When the reaction is carried
out in acetic acid, dione 7 is also present in the reaction mixture (~20% as indicated by the 1H NMR spectrum)
but could not be isolated due to the formation of a larger amount of by-products. In its mass spectrum, the peak
with m/z 541.0 corresponds to molecular ion [M+1]+, which indicates formation of the product of oxidation of
1
compound 5b (m/z 543.0 [M+1]+). All the aromatic proton signals in the H NMR spectrum of dione 7, similar
to the spectrum of dihydro derivative 5b, have double intensity. One of the two-proton signals is seen upfield at
6.54 ppm and was assigned to resonance of the protons H-1 and H-13, which fall in the benzene ring shielding
zone of the substituent at C-14. The signal of the NH group proton is lacking due to exchange with water present
in the DMSO-d6 solvent but the vibrational band for this group is observed in the IR spectrum at 3356 cm-1.
Furthermore, the IR spectrum of dione 7 shows vibrational bands for the C=O groups at  = 1690 and 1684 cm-1.
The condensation of isocarbostyryl 1b with 4-methoxybenzaldehyde in the presence of Me3SiCl gave
only 12-(4-ethoxyphenyl)-10-nitrodibenzo[b,f][1,8]naphthyridin-5(6H)-one (4b), while formation of
intermolecular reaction product 5 could not be detected. The reaction of isocarbostyryl 1b with 4-nitro-
benzaldehyde leads to a complex mixture of unidentified products both in acetic acid and in the presence of
Me3SiCl.
We then studied the reaction of benzaldehydes with 3-HetNH-isoquinolin-1(2H)-ones 2a-f in the
presence of Me3SiCl (Schemes 2 and 3). The reaction of 3-(2-pyridylamino)isoquinolin-1(2H)-one 2a with
benzaldehydes under these conditions is also terminated by intramolecular cyclization, leading to hydrochloride
salts of 13-aryl-6,13-dihydro-5H-pyrido[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-ones 8a-d. In this case, the
pyridine ring nitrogen atom acts as the nucleophilic site in the cyclization step. Salts 8 are stable, and, with the
exception of compound 8d, were isolated as pure compounds. Isoquinoline 8d contained up to 20% impurities,
which could not be removed by recrystallization or chromatography, probably due to the instability of this
compound relative to oxidation. Salts 8a-d are readily converted to bases 9a-d by the action of Et3N (Method
C). The 1H NMR spectra of salts 8a-d and bases 9a-d (Table 3) differ by the position of aromatic proton signals,
which are observed at lower field in the case of salts 8. Protonation leads to increased lability of the NH group
1
proton, whose signals in the H NMR spectra of salts 8a-d are very broadened or not observed due to rapid
exchange. The greatest difference in the IR spectra of salts 8 and bases 9 is noted for the position of C=O group
vibrational band, which is found at 1667-1670 cm-1 for salts 8 and at 1631-1645 cm-1 for bases 9.
The reaction of 3-(2-pyrazinylamino)isoquinolin-1(2H)-one 2b or 3-(1,3-thiazol-2-ylamino)-
isoquinolin-1(2H)-one 2c with 4-alkoxybenzaldehydes proceeds analogously to give 13-(4-methoxyphenyl)-
6,13-dihydro-5H-pyrazino[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one (10) and 12-(4-ethoxyphenyl)-6,12-dihydro-
5H-[1,3]thiazolo[3',2':1,2]pyrimido[4,5-c]isoquinolin-5-one (11a), respectively (Method C). The protic salt of
isoquinolinone 10 is unstable, while in the case of 11a, the corresponding salt 12a contained impurities, which
were probably products of the oxidation of compound 11a.
Heating 3-thiazolylaminoisocarbostyryl 2c with 4-nitrobenzaldehyde in the presence of Me3SiCl for 5 h
leads to a mixture, in which the oxidation product, namely, the hydrochloride salt of 12-(4-nitrophenyl)-5H-
[1,3]thiazolo[3',2':1,2]pyrimido[4,5-c]isoquinolin-5-one (13) is the major product obtained in 72% yield, while
12-(4-nitrophenyl)-6,12-dihydro-5H-[1,3]thiazolo[3',2':1,2]pyrimido[4,5-c]isoquinolin-5-one (11b) was isolated
in low (17%) yield. The yield of dihydro derivative 11b may be increased to 30% by reducing the reaction time
to 1 h (the yield of compound 13 in this case is 51%). The formation of protic salt 12b in both cases could not be
detected by NMR spectroscopy.
A distinguishing feature of the 1H NMR spectrum of salt 13, in addition to the lack of a signal for H-12
proton, is the position of the signal for H-1 proton, which is located in the region shielded by the benzene ring of
the 12-Ar substituent and observed upfield (at 6.85 ppm) relative to the corresponding proton, H-5, in starting
isocarbostyryl 2c (at 7.49 ppm) [12]. The difference in the chemical shifts of these protons ( ~ 0.64)
346

is comparable to the difference noted for compound 7 ( ~ 0.73,  H-5 in starting 1a is 7.27 ppm [9]) and
higher than the difference noted for compounds 4a and 4b ( ~ 0.12 for 4a and  ~ 0.42 for 4b,  H-5 in
starting compound 1b is 7.58 ppm [13]). This behavior may be the result of more efficient conjugation between
the isoquinoline and pyrimidine rings in 13 or, correspondingly, the pyridine ring in compound 7. We should
note the position of the carbonyl group vibrational band CO 1692 cm-1 in the IR spectrum of salt 13, which is in
the same region as for compound 7, in contrast to the appearance of this band in the spectra of the other reaction
products 4, 5, and 8-12 at lower frequencies (1631-1670 cm-1). Furthermore, the IR spectrum of salt 13 has a
strong band at 2583 cm-1, in the region characteristic for SH vibrations, while the weak band at 3126 cm-1
corresponds to the NH group participating in an intermolecular hydrogen bond. In our opinion, these data
indicate the formation of structure 13, in which the labile proton is localized on the sulfur atom.
The carbon atom is the nucleophilic site in the cyclization step in the condensation of 3-HetNH-
isoquinolin-1(2H)-ones 2d and 2e with benzaldehydes (Scheme 3) as in the case of 3-ArNH-isoquinolin-1(2H)-
ones 1a and 1b. In the presence of Me3SiCl, isocarbostyryl 2d is readily converted to 14-phenyl-8,14-dihydro-
benzo[f]isoquino[3,4-b][1,8]naphthyridine-5,9(6H,7H)-dione (14, Method C).
The reaction of aromatic aldehydes with 1,3-dimethylpyrazolyl derivatives 2e leads to a mixture of
reaction products, whose composition depends on the structure of the aldehyde used and reaction heating time.
In the case of heating compound 2e with 4-ethoxybenzaldehyde for only 1 h, the major reaction product is 8,10-
dimethyl-11-(4-ethoxyphenyl)-6,7,8,11-tetrahydro-5H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-one (15a),
while heating for 5 h gives the oxidized product, 11-(4-ethoxyphenyl)-8,10-dimethyl-6,8-dihydro-5H-benzo-
[f]pyrazolo[3,4-b][1,8]naphthyridine-5-one (16a). The content of the second component of the mixture (dihydro
Scheme 3
O
O
O
4
4
1
ArCHO,
Me3SiCl
1) Me3SiCl,
PhCHO
NH
NH
NH
NH
NH
NH
NH
2) Et3N
1
14
2d–f
Het
8
4-EtOC6H4
Ph
N
17
O
ArCHO,
Me3SiCl
14
O
O
4
NH
NH
NH
+
N
1
11
Me
Me
Ar
Ar
N
N
N
N
Me
16a,b
Me
15a,b
O
Me
HN
f Het =
N
e Het =
,
2 d Het =
,
N
N
Me
15, 16 a Ar = 4-EtOC6H4, b Ar = 4-O2NC6H4
347

TABLE 2. IR Spectra of Products 4, 5, and 7-17
Com-
IR spectrum, , cm–1
pound
3148 (NH), 3064, 2980, 1664 (C=O), 1510, 1343, 1245 (C–O), 1049, 820, 761
4a
4b
3137 (NH), 3064, 2986, 1664 (C=O), 1608, 1578 (NO2), 1555, 1504, 1334 (NO2), 1290,
1253 (C–O), 833, 747
3384 (NH), 3059, 2980, 2924, 1664 (C=O), 1606, 1589, 1494, 1253 (C–O), 752
5a
5b
3378 (NH), 3076, 1667 (C=O), 1594 (NO2), 1547, 1497, 1343 (NO2), 1306, 1253 (C–O),
1007, 755
3356 (NH), 3059, 1690 (C=O), 1684 (C=O), 1603, 1592, 1510 (NO2), 1491, 1438,
1348 (NO2), 1329, 1273, 1253 (C–O), 1029, 750, 694
7
3406 (NH), 3064, 2779, 1667 (C=O), 1636, 1550, 1513, 1329, 775
8a
8b
8c
9a
9b
9c
9d
3412 (NH), 3064, 2980, 1670 (C=O), 1636, 1550, 1513, 1262 (C–O), 1175, 769
3384 (NH), 3064, 2980, 1670 (C=O), 1639, 1550, 1513, 1259 (C–O), 1175, 772
3434 (NH), 3028, 1635 (C=O), 1621, 1605, 1515, 1493, 1456, 1333, 1133, 760
3435 (NH), 3070, 2997, 1631 (C=O), 1620, 1603, 1510, 1497, 1253 (C–O), 758
3430 (NH), 3036, 2924, 1636 (C=O), 1617, 1608, 1508, 1500, 1345, 1248 (C–O), 755
3384 (NH), 3070, 1645 (C=O), 1620, 1527 (NO2), 1516, 1497, 1348 (NO2), 1141, 822,
758, 736
3406 (NH), 3059, 1650 (C=O), 1628, 1606, 1527, 1510, 1250 (C–O), 1175, 758
3440 (NH), 3109, 1636 (C=O), 1608, 1510, 1242 (C–O), 1206, 1172, 758
10
11a
13
3126 (NH), 3031, 2773, 2583 (SH), 1692 (C=O), 1611, 1583, 1569, 1524 (NO2), 1348
(NO2), 1320, 1292, 1147, 836, 764, 738
3412 (NH), 3036, 1659 (C=O), 1631, 1608, 1555, 1541, 1429, 1298, 1256, 758, 699
14
3221 (NH), 3165 (NH), 2980, 1667 (C=O), 1648, 1608, 1583, 1510, 1334, 1245 (C–O),
1046, 766
15a
3132 (NH), 2975, 2930, 1667 (C=O), 1580, 1530, 1342, 1245 (C–O), 1043, 604
3154 (NH), 3064, 2924, 1660 (C=O), 1583, 1513 (NO2), 1340 (NO2), 844, 741
3330 (NH), 3199 (NH), 3059, 2980, 1662 (C=O), 1608, 1538, 1508, 1253 (C–O), 769
16a
16b
17
derivative 16a in the former case and tetrahydro derivative 15a in the latter) did not exceed 25%, which
permitted the efficient separation of this mixture by crystallization. Independently of the heating time, the only
product isolated as a pure compound when using 4-nitrobenzaldehyde in this reaction was 6,8-dihydro-5H-
benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-one 16b. The content of 6,7,8,11-tetrahydro derivative 15b in the
reaction mixture (after heating for 1 h) was less than 15% as indicated by 1H NMR spectroscopy.
3-(3-Pyridylamino)isoquinolin-1(2H)-one 2f, which has an electron-deficient heterocycle at the 3-amino
group, is also converted upon the action of 4-ethoxybenzaldehyde in the presence of Me3SiCl into a cyclic
product, namely, 12-(4-ethoxyphenyl)-7,12-dihydroisoquino[3,4-b][1,5]naphthyridin-5(6H)-one (17) in high
(76%) yield. Closure of the dihydropyridine ring at C(2) atom in the 3-aminopyridine fragment of starting
isocarbostyryl 2f is the predominant course of this reaction, which is characteristic for pyridines possessing an
electron-donor substituent at the -position [14]. The structure of naphthyridinone 17 was supported by the two-
dimensional NOESY spectrum.
Thus, the reaction of 3-ArNH- and 3-HetNH-isocarbostyryls with aromatic aldehydes gives 4-arylidene
derivatives of the type 3, which then convert under the reaction conditions (in the presence of Me3SiCl, or in
acetic acid in the case of 3-ArNH-isocarbostyryls 1a and 1b) in aryl-condensed or hetaryl-condensed derivatives
of pyrimido[4,5-c]isoquinoline or benzo[c][1,8]naphthyridine, including derivatives of previously
348

unreported heterocyclic systems, namely, pyrazino[1',2':1,2]pyrimido[4,5-c]isoquinoline, [1,3]thiazolo-
[3',2':1,2]pyrimido[4,5-c]isoquinoline, benzo[f]pyrazolo[3,4-b][1,8]naphthyridine, and isoquino[3,4-b][1,5]-
naphthyridine.
The mechanism of the intramolecular cyclization depends on the structure of substituent at the 3-amino
group of the starting isocarbostyryl and may occur in three directions. For derivatives of 2-aminoazoles or
2-aminoazines (2a-c), the mechanism involves alkylation at the endocyclic nitrogen atom of the Het substituent.
In the other cases, in which there is no nitrogen atom in the -position to the amino group in the Het substituent
(2d-f and 3-ArNH-isocarbostyryls 1a and 1b), the mechanism involves Friedel-Crafts type aromatic
electrophilic substitution or Michael addition at the -position of the enamine fragment of a second
isocarbostyryl molecule, while nucleophilic substitution of one of the 3-amino groups in the intermediate adduct
leads to a cyclic product. The latter cyclization mechanism is more characteristic for 3-ArNH-isocarbostyryls 1a
and 1b and may be the predominant reaction pathway when using benzaldehydes with an electron-withdrawing
ring substituent. This behavior can likely be attributed to lower stability of the intermediate -complex (18,
Scheme 1) and, as a consequence, increased likelihood of intermolecular alkylation.
EXPERIMENTAL
1
The IR spectra were taken on a Perkin-Elmer Spectrum BX spectrometer for KBr pellets. The H and
13C NMR spectra and HMQC and HMBC heteronuclear correlation experiments were carried out on a Varian
Mercury-400 spectrometer at 400 and 100 MHz, respectively. In all cases, DMSO-d6 was the solvent and TMS
was the internal standard. The melting points were determined on a Boetius block and were uncorrected. The
purity of the products was monitored by HPLC/MS on an Agilent 1100 instrument with an Agilent LC/MSD SL
selective detector (the sample was introduced in a TFA matrix) using electron impact. The physicochemical
characteristics and the elemental analysis data of the products are given in Tables 1-3.
3-(4-Methoxyanilino)isoquinolin-1(2H)-one (1a) was obtained according to Ali et al. [8], while 3-(4-
nitroanilino)isoquinolin-1(2H)-one (1b) was obtained according to our previous procedure [13] and 3-HetNH-
isoquinolin-1(2H)-ones 2a-f were obtained according to our recent procedure [12].
Condensation in Acetic Acid (General Method). A. 4-Ethoxybenzaldehyde or 4-nitrobenzaldehyde
(2.1 mmol) was added to a solution of 3-(arylamino)-1(2H)-isoquinolinone 1a,b (2 mmol) in acetic acid (10 ml)
and heated at reflux for 3-4 h. The solvent was evaporated and 10 ml diethyl ether was added to the residue. The
precipitate was filtered off.
Condensation in the Presence of Me3SiCl (General Method). B. Me3SiCl (0.87 g, 8 mmol) was
added dropwise to a solution of 3-(arylamino)-1(2H)-isoquinolinone 1a,b or 3-(hetarylamino)isoquinolin-1(2H)-
one 2a-f (2 mmol) and aromatic aldehyde (2.1 mmol) in dry DMF (5 ml) and heated on a water bath at 90-95°C
for 4-5 h. The reaction product precipitated upon heating the reaction mixture at reflux or after cooling. The
precipitate was filtered off and washed with ethanol. If a precipitate did not form, the solvent was evaporated in
vacuum and water (20 ml) was added to the residue. The precipitate formed was filtered off and washed with
ethanol.
C. This procedure was carried out according to Method B. Then, the solid was dissolved in 5 ml DMF
and 0.5 ml Et3N was added. The mixture was maintained for 10 min at room temperature and then 20 ml water
was added. The precipitate formed was filtered off and washed with ethanol.
12-Aryl-10-methoxybenzo[b,f][1,8]naphthyridin-5(6H)-ones 4a,b. Product 4a was obtained by
Method A or B (see procedure for the preparation of compound 5a). Product 4b was obtained by Method B.
14-(4-Ethoxyphenyl)-7-(4-methoxyphenyl)-8,14-dihydrobenzo[f]isoquino[3,4-][1,8]naphthyridine-
5,9(6H,7H)-dione (5a) was obtained by Method B. The solvent was evaporated to give a mixture of 4a and 5a,
349

350

351

352

which was then heated to reflux in 5 ml 1:1 acetonitrile–ethanol. The precipitate was filtered off and washed
with hot ethanol to give dione 5a. Cooling the filtrate gave a precipitate of compound 4a, which was filtered off
and washed with ethanol.
7-(4-Methoxyphenyl)-14-(4-nitrophenyl)-8,14-dihydrobenzo[f]isoquino[3,4-b][1,8]naphthyri-dine-
5,9(6H,7H)-dione (5b) was obtained by Method A or B (see procedure for the preparation of dione 7).
7-(4-Methoxyphenyl)-14-(4-nitrophenyl)benzo[f]isoquino[3,4-b][1,8]naphthyridine-5,9(6H,7H)-dione
(7) was obtained by Method B. Reaction product 7 was obtained as a precipitate upon heating the reaction
mixture at reflux. The precipitate was filtered off and washed with hot ethanol. Cooling the filtrate gave a
precipitate of dione 5b, which was filtered off and washed with ethanol.
13-Aryl-6,13-dihydro-5H-pyrido[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one Hydrochloride (8a-c)
and 12-(4-Ethoxyphenyl)-7,12-dihydroisoquino[3,4-b][1,5]naphthyridin-5(6H)-one Hydrochloride (17)
were obtained by Method B.
13-Aryl-6,13-dihydro-5H-pyrido[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-ones (9a-d), 13-(4-methoxy-
phenyl)-6,13-dihydro-5H-pyrazino[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one (10), 12-(4-ethoxyphenyl)-6,12-di-
hydro-5H-[1,3]thiazolo[3',2':1,2']pyrimido[4,5-c]isoquinolin-5-one (11a), and 14-phenyl-8,14-dihydrobenzo-
[f]isoquino[3,4-b][1,8]naphthyridine-5,9(6H,7H)-dione (14) were obtained according to Method C.
12-(4-Nitrophenyl)-6,12-dihydro-5H-[1,3]thiazolo[3',2':1,2]pyrimido[4,5-c]isoquinolin-5-one (11b)
was obtained by Method B. The heating time was 1 h. The precipitate formed during heating of the solution at
reflux was filtered off the hot solution and washed with acetone to give compound 13 in 51% yield.
Isoquinolinone 11b was separated from the filtrate by Method C.
12-(4-Nitrophenyl)-5H-[1,3]thiazolo[3',2':1,2]pyrimido[4,5-c]isoquinolin-5-one
Hydrochloride
(13) was obtained by Method B. The heating time was 5 h. The precipitate formed during heating of the solution
at reflux was filtered off the hot solution and washed with acetone to give compound 13. Isoquinolinone 11b
was separated in 17% yield from the filtrate by Method C.
11-(4-Ethoxyphenyl)-8,10-dimethyl-6,7,8,11-tetrahydro-5H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-
5-one (15a) was obtained by Method B. The heating time was 1 h. The precipitate formed during heating of the
solution at reflux was filtered off the hot solution and washed with hot ethanol to give 16a in 20% yield. The
filtrate was evaporated in vacuum and 20 ml water was added to the residue. The precipitate of naphthyridinone
15a was filtered off and washed with ethanol.
11-Aryl-8,10-dimethyl-6,8-dihydro-5H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-ones
16a,b
were obtained by Method B. The heating time was 5 h. The precipitate of 6,8-dihydrobenzo[f]pyrazolo-
[3,4-b][1,8]naphthyridinone 16a,b formed upon heating the solution at reflux was filtered off the hot solution
and washed with hot ethanol. In the case of the reaction with 4-ethoxybenzaldehyde, naphthyridinone 15a was
separated from the filtrate in 22% yield (see procedure above).
REFERENCES
1.
L. M. Potikha, V. V. Sypchenko, and V. A. Kovtunenko, Khim. Geterotsikl. Soedin., 1360 (2010).
[Chem. Heterocycl. Comp., 46, 1096 (2010)].
2.
3.
V. Granik, V. Makarov, and C. Parkanyi, Adv. Heterocycl. Chem., 72, 283 (1998).
V. A. Kovtunenko, L. M. Potikha, and R. M. Gutsul, Zh. Org. Farmatsevt. Khim., 7, No. 4(28), 5,
(2009).
4.
5.
S. Ohta, S. Kimoto, and M. Okamoto, Yakugaku Zasshi, 92, 1479 (1972); Ref. Zh. Khim., 19, Zh280
(1973).
S. Ohta, S. Kimoto, and M. Okamoto, Yakugaku Zasshi, 92, 1473 (1972); Chem. Abstr., 78, 97517
(1973).
353

6.
7.
8.
9.
L. W. Deady, N. H. Quazi, and H. Nurul, J. Heterocycl. Chem., 31, 793 (1994).
M. F. Sartori, A. Oken, and H. E. Schroeder, J. Org. Chem., 31, 1498 (1966).
M. I. Ali, A. A. El-Sayed, Abd-Elsamel. M. Abd-Elfattah, J. Org. Chem., 37, 3209 (1972).
L. M. Potikha, R. Gutsul, V. A. Kovtunenko, and A. V. Turov, Khim. Geterotsikl. Soedin., 718 (2010).
[Chem. Heterocycl. Comp., 46, 569 (2010)].
10.
11.
12.
S. V. Ryabukhin, A. S. Plaskon, D. M. Volochnyuk, S. E. Pipko, A. N. Shivanyuk, and
A. A. Tolmachev, J. Comb. Chem., 9, 1073 (2007).
S. V. Ryabukhin, A. S. Plaskon, A. V. Tverdokhlebov, and A. A. Tolmachev, Synth. Commun., 34, 1483
(2004).
L. M. Potikha, R. M. Gutsul, V. A. Kovtunenko, and A. A. Tolmachev, Khim. Geterotsikl. Soedin., 575
(2010) [Chem. Heterocycl. Comp., 46, 457 (2010)].
13.
14.
T. T. Kucherenko, R. Gutsul, V. M. Kisel, and V. A. Kovtunenko, Tetrahedron, 60, 211 (2004).
O. S. Tee and M. Paventi, J. Am. Chem. Soc., 104, 4142 (1982).
354